Project Summary/Abstract The aim of the research described in this proposal is to develop a series of unique and innovative complexes to translate metalloenzyme active site reactivity and selectivity to the realm of synthetic constructs for the study biologically relevant reactions. Many metalloenzymes catalyze reactions that involve either oxidation or reduction of substrate, vital for maintaining human health, and these chemical transformations are generally multi-electron redox processes. The protein environment plays a significant role in the regulation of the reduction potentials to match the specified chemistry of the active site through the use of H-bonding and redox-active amino acids located in the secondary coordination sphere. In other words, the function of health-related metalloenzymes can be understood within the context of changes in the environments proximal to the metal center(s). One glaring weakness of many biomimetic systems is the inability to regulate both the protonation state and the reduction potential of the active site. We plan to overcome these weaknesses by integrating a proton responsive secondary coordination sphere and ligand-based redox-active sites within a single metal- ligand construct. The hypothesis is that by utilizing the redox-active pyridinediimine (PDI) scaffold, it will be possible to unburden the proton-responsivity of the complex from the ligand-based redox-active sites to independently tune both the structural properties of the metal-ligand scaffolds (secondary coordination sphere) and the redox properties (ligand-based redox active sites). We propose that this approach is an effective way to model the reactivity of natural metalloenzymes. Ultimately, the results from this research will lead to a new class of bioinspired complexes that display the elegant control over reactivity that is observed by metalloenzymes. Specific Aims include: (1) Develop a class of bioinspired metal-ligand complexes based on the PDI scaffold that contain proton-responsive secondary coordination spheres. (2) Probe the relationship between the ligand protonation state and the ligand-based redox-active sites. (3) Leverage the proton-responsive secondary coordination sphere and ligand-based redox sites for small molecule activation.